cancers

Article

Phase I/Ib Study of Tenalisib (RP6530), a Dual PI3Kδ/γ Inhibitor in Patients with Relapsed/RefractoryT-Cell Lymphoma

Auris Huen 1 , Bradley M. Haverkos 2, Jasmine Zain 3, Ramchandren Radhakrishnan 4,Mary Jo Lechowicz 5, Sumana Devata 6, Neil J. Korman 7, Lauren Pinter-Brown 8,Yasuhiro Oki 9, Prajak J. Barde 10, Ajit Nair 10, Kasi Viswanath Routhu 10,Srikant Viswanadha 10, Swaroop Vakkalanka 10 and Swaminathan P. Iyer 11,*

1 Department of Dermatology, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA;aohuen@mdanderson.org

2 Department of Medicine, Division of Hematology, University of Colorado, Denver, CO 80204, USA;BRADLEY.HAVERKOS@cuanschutz.edu

3 Department of Lymphoma, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;jazain@coh.org

4 Department of Lymphoma, the University of Tennessee Graduate School of Medicine, Knoxville, TN 37920,USA; RRamchandren@utmck.edu

5 Department of Lymphoma, Emory University, Atlanta, GA 30322, USA; mlechow@emory.edu6 Medical College of Wisconsin. Previously with Department of Internal Medicine, University of Michigan,

Ann Arbor, MI 48109, USA; sdevata@mcw.edu7 Department of Dermatology, Case Western Reserve University and University Hospitals Cleveland Medical

Center, Cleveland, OH 44106, USA; Neil.Korman@uhhospitals.org8 Department of Medicine and Dermatology, Chao Family Comprehensive Cancer Center University of

California, Irvine, CA 92868, USA; lpinterb@uci.edu9 Genentech Inc. Previously with Department of Lymphoma and Myeloma, the University of Texas M.D.

Anderson Cancer Center, Houston, TX 77030, USA; okiyasuhiro@gmail.com10 Rhizen Pharmaceuticals S.A., CH-2300 La Chaux-de-Fonds, Switzerland; pjb@rhizen.com (P.J.B.);

an@rhizen.com (A.N.); kr@rhizen.com (K.V.R.); srikantv@rhizen.com (S.V.); sv@rhizen.com (S.V.)11 Department of Lymphoma and Myeloma, the University of Texas, MD Anderson Cancer Center, Houston,

TX 77030, USA* Correspondence: SPIyer@mdanderson.org; Tel.: +1-713-792-5242; Fax: +1-713-673-8381

Received: 24 July 2020; Accepted: 12 August 2020; Published: 15 August 2020�����������������

Abstract: Tenalisib (RP6530), a dual phosphoinositide 3-kinase δ/γ inhibitor was evaluated in aphase I/Ib study for maximum tolerated dose (MTD), pharmacokinetics, and efficacy in patients withrelapsed/refractory peripheral and cutaneous T-Cell Lymphoma (TCL). Histologically confirmed(TCL) patients, with ≥1 prior therapy received Tenalisib orally in a 28-day cycle in doses of 200to 800 mg twice daily (800 mg in fasting and fed state) in escalation phase (n = 19) and 800 mgtwice daily (fasting) in expansion phase (n = 39). The most frequently reported treatment emergentadverse events (TEAE) and related TEAE were fatigue (45%) and transaminase elevations (33%),respectively. Most frequently reported related Grade ≥3 TEAE was transaminase elevation (21%).Two dose-limiting toxicities occurred in the 800 mg fed cohort; hence, 800 mg fasting dose wasdeemed MTD. Tenalisib was absorbed rapidly with a median half-life of 2.28 h. Overall responserate in 35 evaluable patients was 45.7% (3 complete response (CR); 13 partial response (PR)) andmedian duration of response was 4.9 months. Responding tumors showed a marked downregulationof CD30, IL-31 and IL-32α. With an acceptable safety and promising clinical activity, Tenalisib can bea potential therapeutic option for relapsed/refractory TCL. Currently, a phase I/II combination studywith romidepsin is ongoing.

Cancers 2020, 12, 2293; doi:10.3390/cancers12082293 www.mdpi.com/journal/cancers

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Keywords: maximum tolerated dose; dose limiting toxicity; PTCL; CTCL

1. Introduction

Peripheral T-cell lymphomas (PTCL) comprises of a heterogeneous group of lymphoidmalignancies and represent approximately 12% of all non-Hodgkin lymphomas (NHLs) [1]. In theUnited States, PTCL not otherwise specified (PTCL-NOS) and cutaneous T-cell lymphoma (CTCL) arethe most common subtypes, accounting for 15% and 27% of PTCL and CTCL cases, respectively [2–5].The majority of PTCLs have an aggressive behavior and poor outcomes with an overall five-yearsurvival rate of 30% [5–7]. CTCLs are generally indolent, with a subset having poorer outcomes.Relapsed/refractory patients with advanced-stage CTCL are usually resistant to chemotherapyand clinical response is achieved in only 30% to 40% of patients, displaying poor prognosis [8,9].The Food and Drug Administration (FDA) approved single agents have an overall response rate(ORR) of about 30% (pralatrexate—29%, romidepsin—25%, belinostat—26%) except for brentuximabvedotin (ORR—68%) in CD30+ T-cells [10–12]. However, given the aggressive nature of PTCL andadvanced-stage CTCL, novel therapeutic agents targeting critical pathways are needed to achievebetter disease control in these patients.

Phosphatidylinositol 3-kinase (PI3K) is an important cellular signaling protein. The δ and γ

isoforms are predominantly expressed in cells of hematopoietic origin. Modulation of this pathway byPI3K inhibitors can regulate several downstream events that drive the oncogenic processes such as cellproliferation, migration, and survival. Studies have also validated the PI3K-protein kinase B (AKT)pathway as a potential therapeutic target in PTCL [13–16].

Tenalisib (RP6530) is a novel, orally available, dual PI3K δ/γ inhibitor with nanomolar inhibitorypotency and several fold selectivity over α and β PI3K isoforms. It has demonstrated apoptotic andanti-proliferative activity in patient-derived primary cell lines representative of B and T lymphomacell lines [17]. It has also demonstrated efficacy in a mouse T-cell leukemia xenograft model and hasshown ex-vivo activity in malignant patient derived primary CTCL cells [18].

Tenalisib was evaluated previously in a phase I study in patients with relapsed/refractoryhematological malignancies and demonstrated acceptable safety and promising efficacy [19]. Based onthe preliminary findings in patients with hematological malignancies, a phase I/Ib study was performedin patients with relapsed/refractory TCL.

2. Methods

2.1. Study Design

This was a two-part phase I/Ib multicenter study conducted across eight sites in the US. The first partwas a phase I, open-label, 3 + 3 dose escalation, maximum tolerated dose (MTD) determination studyin patients with relapsed/refractory T Cell Lymphoma. In this phase, both PTCL and CTCL patientswere enrolled together across all cohorts. The second part was phase Ib, open label, dose expansionphase which was initiated after the MTD dose was confirmed. In this part, separate cohorts of PTCLand CTCL were enrolled. (ClinicalTrials.gov identifier: NCT02567656).

The study was planned to enroll up to 58 patients. The primary objective was to evaluatethe safety, MTD and pharmacokinetics (PK) of Tenalisib. Secondary objectives were to evaluatethe pharmacodynamic effects, the anti-tumor activity [ORR defined by complete response (CR) andpartial response (PR) rates] and duration of response (DoR). Correlation of treatment outcomes withbiomarkers were exploratory objectives.

The study protocol (RP6530-1401) was first approved by the Institutional Review Board (IRB)(Ethical code-2015-0130) of MD Anderson Cancer Center on 24 September 2015 and subsequentlyby other respective IRBs and was conducted according to the standards of Good Clinical Practice

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outlined in the International Council for Harmonization E6 (ICH E6) Tripartite Guideline, Declarationof Helsinki, and Code of Federal Regulation (CFR) Title 21 part 312. Written informed consent wasobtained from all patients prior to enrollment in the study.

2.2. Eligibility Criteria

The entry criteria for patients with histologically confirmed relapsed/refractory CTCL/PTCL,included those who received one or more prior treatment lines, but not eligible for transplantation orstandard/approved therapies and have radiologically measurable or skin evaluable disease.

Key inclusion criteria were age ≥18 years, life expectancy ≥12 weeks, eastern cooperative oncologygroup (ECOG) performance status ≤2, and adequate organ function. Adequate organ functionwere defined as hemoglobin ≥8 g/dL, absolute neutrophil count (ANC) ≥0.75 × 109/L, platelets≥50 × 109/L, total bilirubin ≤1.5 times the upper limit of normal (ULN), alanine aminotransferase(ALT), and aspartate aminotransferase (AST) ≤2.5 × ULN if no liver involvement or 5 × ULN withliver involvement, and creatinine ≤2.0 mg/dL or calculated creatinine clearance ≥50 mL/min.

The key exclusion criteria were prior cancer therapy in the last three weeks or within fivehalf-lives of that agent, whichever was shorter, stem cell transplantation (autologous-SCT within threemonths and allogeneic-SCT within 12 months), prior use of PI3K/mammalian target of rapamycininhibitor/AKT/bruton tyrosine kinase inhibitor in the last 6 months, any investigational drug in the lastfour weeks, or current use of immunosuppressive therapy. In addition, patients with liver disease,uncontrolled severe infections/medical conditions, other active cancers, and pregnant and lactatingwomen were also excluded.

2.3. Study Treatment

Tenalisib tablets were administered twice daily (BID) in a 28-day cycle. In the fasting cohorts,patients fasted 2 h before and 1 h after the drug administration. In the fed cohort, patients took tablets30 min after breakfast and dinner. The starting dose of Tenalisib was 200 mg BID. The subsequentplanned doses were 400 mg BID and 800 mg BID. The dosing schedule was chosen based on the shortelimination half-life. The dose escalation continued until the MTD/optimal dose was identified basedon dose limiting toxicities (DLT) and Cycle 1 Day (C1D1) PK data. The dose expansion phase wasinitiated once the MTD/optimal dose was confirmed. The planned enrollment was 20 patients in eachof CTCL and PTCL cohorts for a total of 58 patients.

Treatment was continued in patients experiencing clinical benefit for two years unless there wasprogression of disease or toxicity which warranted discontinuation of therapy. All patients who showedCR, PR or Stable Disease (SD) and completed two years of treatment were moved to compassionateuse protocol and followed [20].

2.4. Dose Limiting Toxicities

Protocol defined hematological or non-hematological toxicity was considered dose-limiting ifit occurred during the first cycle (within the first 28 d) and was considered related to Tenalisib.Hematological DLTs was defined as Grade 4 anemia; Grade 4 neutropenia for >7 days, or Grade ≥3febrile neutropenia with fever >38.5 ◦C [101 ◦F]; Grade 4 thrombocytopenia for >7 days, or Grade≥3 thrombocytopenia associated with Grade >2 bleeding. Non-hematological DLTs were Grade ≥3toxicity with exception of Grade ≥3 diarrhea or nausea that did not resolve to ≤Grade 2 within 48 hdespite treatment, and ≥1.5 ULN of bilirubin or >3 ALT/AST elevation that did not resolve to ≤Grade 1within 7 d, or treatment delay for ≥ 14 d due to unresolved toxicity.

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2.5. Assessments

2.5.1. Safety Assessment

Safety assessment included adverse event (AE) and serious adverse events (SAE) as per CommonTerminology Criteria for Adverse Events (CTCAE), Version 4.03. During dose escalation, safetyassessments were performed at weekly intervals during Cycle 1 and Cycle 2 and at two weeklyintervals during Cycle 3 and 4. After completion of Cycle 4, safety assessments were performed onDay 1 of each subsequent cycle. In dose expansion phase, all safety assessments were performed onDay 1 of each cycle.

2.5.2. Pharmacokinetic (PK) Assessments

Complete PK assessments were performed during dose escalation on Day 1 of Cycle 1 and 2and pre-dose at other time points (pre-dose on Day 8 and Day 15 of Cycle 1 and 2, Day 1 and Day15 of Cycle 3 and 4 and pre-dose on Cycle 5 and beyond). In the dose expansion phase, sampleswere collected pre-dose on Day 1 from Cycle 1 to Cycle 8. The PK parameters included maximumplasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the plasmaconcentration-time curve from time of administration to the end of the dosing interval (AUC(0-τ)),apparent oral drug clearance during a dosing interval (CLss/F), apparent volume of distribution duringa dosing interval (Vz/F) and elimination half-life (t1/2) were evaluated.

2.5.3. Efficacy Assessments

Efficacy assessments included radiological, bone marrow biopsy/aspiration and skin assessments.In some cases, bone marrow disease alone was used for disease assessment. In these cases, responsewas reported as CR or non-CR.

In PTCL patients, radiological assessment was performed at screening, Day 1 of Cycle 3 and 5 andapproximately 12 weeks thereafter. Assessments of skin lesions in PTCL patients were performed,if applicable. Bone marrow biopsy/aspirate was performed in patients without measurable butassessable disease at screening and on Day 1 of Cycle 3 and 5, then also approximately 12 weeksthereafter to confirm a CR.

In CTCL patients, assessment of skin lesions was performed at screening, Day 1 of Cycle 3 and 5,approximately 12 weeks thereafter and at the end of treatment (EOT). Skin photographs were obtainedfor half body global and up to 5 selected representative index lesions at baseline, at Day 1 of Cycle3, EOT, at PR/CR/progressive disease (PD) and as required as per the discretion of the Investigator.In case of nodal involvement, radiological assessment was performed at screening, Day 1 of Cycle 3and 5 and approximately 12 weeks thereafter. Skin biopsy was performed from the most induratedarea at screening, on C3D1 and to confirm a CR. Patients with predominantly blood involvement had abone marrow biopsy at screening and as indicated to confirm a CR.

The efficacy parameters included ORR and DoR. Revised Response Criteria for MalignantLymphoma (Cheson 2007) was used for evaluation of PTCL [21]. International Society for CutaneousLymphomas Response Criteria for Mycosis Fungoides and Sezary Syndrome (SS) and CutaneousLymphoma Task Force of the European Organization for Research and Treatment of Cancer criteriawere used for evaluation of CTCL patients [22]. For skin scoring, the modified Severity WeightedAssessment Tool was used. For local index lesion skin scoring, the Composite Assessment of IndexLesion Severity was used.

2.5.4. Pharmacodynamic Assessment

Biomarker phosphorylated-AKT (pAKT) was to be estimated in five Sezary syndrome patientsfrom single center (MD Anderson Cancer Centre, Houston, TX, USA) in dose escalation phase. Sampleswere to be collected pre-dose and after 1 h on Day 1 of Cycle 1, pre-dose on Day 8 and 22 of Cycle 1,Day 1 of Cycle 2 and 3 and at EOT.

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2.5.5. Correlative Biomarker Analysis

Assessment of CD30 and soluble IL-2 receptor (sIL-2R) for PTCL and cutaneous T-cell attractingchemokine (CTACK), IL-31 and IL-32α for CTCL were performed in plasma at screening, pre-dose andafter 1 h on Day 1 of Cycle 3, at EOT and/or to confirm a response.

2.6. Statistical Analysis and Sample Size

No formal sample size calculation was performed for this dose escalation followed by doseexpansion study. The safety population included all patients who received at least one dose of studymedication. PK population included all patients of the safety population who provided at least oneblood draw. Efficacy population included all patients of the safety population who provided at leastone post-baseline disease assessment.

All statistical analyses were performed using SAS 9.2 (SAS Institute (India) Pvt. Ltd., Mumbai,Maharashtra, India). Descriptive statistics were provided in the summary tables as per the dose cohort.Quantitative variables were summarized by using N, arithmetic means, standard deviation, medianand range. Categorical variables were summarized by using frequency distributions and percentages,and 95% confidence intervals when applicable.

3. Results

3.1. Patient Disposition and Baseline Characteristics

From October 2015 to December 2018, a total of 59 patients were enrolled across the dose escalationand expansion cohorts of which 58 patients (28 (48.3%) PTCL and 30 (51.7%) CTCL) received at leastone dose of Tenalisib. Nineteen patients (9 PTCL, 10 CTCL) were enrolled in 4 cohorts of dose escalationphase [Cohort 1: 200 mg, n = 4; Cohort 2: 400 mg BID n = 4; Cohort 3: 800 mg BID (fasting) n = 5;and Cohort 4: 800 mg BID (fed), n = 6] and thirty-nine patients (19 PTCL and 20 CTCL) in expansionphase (800 mg BID fasting) in a 28-day cycle. In dose escalation phase, patients in cohort 1 to 3 receivedTenalisib in a fasting state and Cohort 4 received Tenalisib in fed state (Figure 1).

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2.5.5. Correlative Biomarker Analysis

Assessment of CD30 and soluble IL-2 receptor (sIL-2R) for PTCL and cutaneous T-cell attracting

chemokine (CTACK), IL-31 and IL-32α for CTCL were performed in plasma at screening, pre-dose

and after 1 h on Day 1 of Cycle 3, at EOT and/or to confirm a response.

2.6. Statistical Analysis and Sample Size

No formal sample size calculation was performed for this dose escalation followed by dose

expansion study. The safety population included all patients who received at least one dose of study

medication. PK population included all patients of the safety population who provided at least one

blood draw. Efficacy population included all patients of the safety population who provided at least

one post-baseline disease assessment.

All statistical analyses were performed using SAS 9.2 (SAS Institute (India) Pvt. Ltd., Mumbai,

Maharashtra, India). Descriptive statistics were provided in the summary tables as per the dose

cohort. Quantitative variables were summarized by using N, arithmetic means, standard deviation,

median and range. Categorical variables were summarized by using frequency distributions and

percentages, and 95% confidence intervals when applicable.

3. Results

3.1. Patient Disposition and Baseline Characteristics

From October 2015 to December 2018, a total of 59 patients were enrolled across the dose

escalation and expansion cohorts of which 58 patients (28 (48.3%) PTCL and 30 (51.7%) CTCL)

received at least one dose of Tenalisib. Nineteen patients (9 PTCL, 10 CTCL) were enrolled in 4

cohorts of dose escalation phase [Cohort 1: 200 mg, n = 4; Cohort 2: 400 mg BID n = 4; Cohort 3: 800

mg BID (fasting) n = 5; and Cohort 4: 800 mg BID (fed), n = 6] and thirty-nine patients (19 PTCL and

20 CTCL) in expansion phase (800 mg BID fasting) in a 28-day cycle. In dose escalation phase, patients

in cohort 1 to 3 received Tenalisib in a fasting state and Cohort 4 received Tenalisib in fed state (Figure 1).

Figure 1. Disposition of subjects.

The median age of the patients was 67 years. Males were 52% and females 48%. Stage IV was the

most common stage in both PTCL (18 patients) and CTCL (12 patients). All patients received one or

more prior cancer therapies with 81% patients having received ≥3 prior therapies. ECOG performance

Figure 1. Disposition of subjects.

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The median age of the patients was 67 years. Males were 52% and females 48%. Stage IV was themost common stage in both PTCL (18 patients) and CTCL (12 patients). All patients received one ormore prior cancer therapies with 81% patients having received ≥3 prior therapies. ECOG performancestatus was 0, 1, and 2 in 41%, 53% and 5% patients, respectively. The disease status was refractory tothe last prior therapy in 38 (66%) patients whereas 20 (35%) patients had relapsed after receiving lastprior therapy. The demographic and baseline characteristics for all patients who received Tenalisib aregiven in Table 1.

Table 1. Demography and baseline characteristics.

CharacteristicDose Escalation Dose Expansion

TotalCTCL PTCL CTCL PTCL

Sex/Gender, N (%)Male 6 (60.0%) 5 (55.6%) 7 (35.0%) 12 (63.2%) 30 (51.7%)

Female 4 (40.0%) 4 (44.4%) 13 (65.0%) 7 (36.8%) 28 (48.3%)

Race, N (%)White/Caucasian 10 (100.0%) 9 (100.0%) 16 (80.0%) 14 (73.7%) 49 (84.5%)

Asian 0 0 0 1 (5.3%) 1 (1.7%)Afro-American 0 0 4 (20.0%) 4 (21.1%) 8 (13.8%)

Age (years)Mean 69.4 57.6 63.4 68.9 65.4

Median 69.4 55.9 67. 63.9 67.1Range 60.7–76.6 40.9–73.2 39.5–84.5 45.7–89.5 39.5–89.5

Diagnosis, N (%)PTCL 0 9 (100.0%) 0 19 (100.0%) 28 (48.3%)CTCL 10 (100.0%) 0 20 (100.0%) 0 30 (51.7%)

ECOG Performance Status Score,N (%)

0 10 (100.0%) 2 (22.2%) 7 (35.0%) 5 (26.3%) 24 (41.4%)1 0 6 (66.7%) 12 (60.0%) 13 (68.4%) 31 (53.4%)2 0 1 (11.1%) 1 (5.0%) 1 (5.3%) 3 (5.2%)

Disease Status, N (%)Relapse after last treatment 5 (50.0%) 3 (33.3%) 3 (15.0%) 9 (47.4%) 20 (34.5%)Refractory to last treatment 5 (50.0%) 6 (66.7%) 17 (85.0%) 10 (52.6%) 38 (65.5%)

Stage of the Disease, N (%)Stage I 3 (30.0%) 0 7 (35.0%) 1 (5.3%) 11 (18.9%)Stage II 1 (10.0%) 1 (11.1%) 4 (20.0%) 1 (5.3%) 7 (12.1%)Stage III 0 3 (33.3%) 3 (15.0%) 4 (21.1%) 10 (17.2%)Stage IV 6 (60.0%) 5 (55.6%) 6 (30.0%) 13 (68.4%) 30 (51.7%)

Prior therapies, N (%)Therapy ≥ 3 9 (90.0%) 8 (88.9%) 18 (90.0%) 12 (63.2%) 47 (81.0%)Therapy ≥ 5 8 (80.0%) 4 (44.4%) 13 (65.0%) 2 (10.5%) 27 (46.6%)

N = Number of patients; PTCL = Peripheral T-cell lymphoma; CTCL = Cutaneous T-cell lymphoma; ECOG = Easterncooperative oncology group.

3.2. Safety

The median duration of exposure in the dose escalation phase was 99 d (range 0.8 to 641 d) and inthe dose expansion phase was 67 d (range 13 to 644 d). Safety assessment of 58 patients receiving atleast one dose of Tenalisib demonstrated an acceptable safety profile. In the dose escalation phase,no DLTs were noted in fasting Cohorts 1, 2, and 3. Two DLTs (Grade 3 ALT increased and Grade 3erythematous rash) were observed in Cohort 4 (fed) and hence this dose was considered exceedingthe MTD. The dose of 800 mg BID (fasting) was considered as MTD and dose expansion phase wasinitiated with this dose.

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Twelve patients (four in dose escalation phase and eight in dose expansion phase) completed atleast 8 cycles while others were discontinued prior to Cycle 8. Four patients of dose expansion phasewere rolled over to the compassionate medication study. The most common reason for discontinuationwas disease progression (61%) followed by adverse events (9%), consent withdrawal (9%), investigator’sdiscretion (9%), intercurrent illness (3%) and non-compliance to trial requirements (2%).

Overall, 57 (98%) patients had at least one treatment emergent adverse event (TEAE) of which 45(78%) patients had at least one related TEAE [17 (90%) in dose escalation phase and 28 (72%) in doseexpansion phase]. In both phases the most frequently reported TEAE was fatigue reported in 26 (45%)patients. This was followed by AST increase in 21 patients (36%), ALT increase in 20 patients (35%) anddiarrhea in 19 patients (33%) (Table 2). Among the related TEAEs, 7 (37%) patients in dose escalationphase and 17 (41%) patients in dose expansion phase reported Grade 3 TEAEs, while three (5.2%)patients in dose expansion phase reported Grade 4 TEAEs. All other related TEAEs were of Grade1/2 in intensity (Table S1). Transaminase elevations (21%) were the most frequently reported relatedGrade ≥3 TEAE in both phases and most of the events were reported within Cycle 2. Anemia (8.6%),neutropenia (6.9%) and hyponatremia (6.9%) were the other Grade 3 TEAEs (Table 3). Grade 4 relatedTEAEs included two events of ALT increase and one event of sepsis. Most of these AEs were reversedby withholding the dose of Tenalisib and with supportive management. Additionally, steroids wereused in nine patients to manage elevated ALT/AST. None of the related TEAEs led to a fatal outcome.

Table 2. Incidence of adverse event (AE) (AE ≥ 10%) reported in the study (relationship-all).

System Organ Class (SOC) and Preferred term (PT)Dose Escalation Dose Expansion Total

(N = 19) (N = 39) (N = 58)n (%), E n (%), E n (%), E

Gastrointestinal disordersDiarrhea 5 (26.3%), 6 14 (35.9%), 19 19 (32.8%), 25Nausea 6 (31.6%), 7 9 (23.1%), 9 15 (25.9%), 16

Constipation 4 (21.1%), 5 5 (12.8%), 5 9 (15.5%), 10Vomiting 4 (21.1%), 5 5 (12.8%), 6 9 (15.5%), 11

Abdominal pain 3 (15.8%), 3 5 (12.8%), 6 8 (13.8%), 9

General disorders and administration site conditionsFatigue 8 (42.1%), 8 18 (46.2%), 19 26 (44.8%), 27Pyrexia 4 (21.1%), 4 9 (23.1%), 17 13 (22.4%), 21

Metabolism and nutrition disordersDecreased appetite 5 (26.3%), 5 7 (17.9%), 8 12 (20.7%), 13

Dehydration 3 (15.8%), 5 10 (25.6%), 13 13 (22.4%), 18Hyponatremia 4 (21.1%), 4 4 (10.3%), 5 8 (13.8%), 9Hypokalemia 4 (21.1%), 5 3 (7.7%), 5 7 (12.1%), 10

InvestigationsAspartate aminotransferase increased 7 (36.8%), 16 14 (35.9%), 21 21 (36.2%), 37Alanine aminotransferase increased 6 (31.6%), 13 14 (35.9%), 20 20 (34.5%), 33

Gamma-glutamyl transferase increased 2 (10.5%), 2 6 (15.4%), 9 8 (13.8%), 11Blood creatinine increased 1 (5.3%), 1 6 (15.4%), 6 7 (12.1%), 7

Blood thyroid stimulating hormone increased 2 (10.5%), 2 4 (10.3%), 5 6 (10.3%), 7

Nervous system disordersDizziness 3 (15.8%), 3 7 (17.9%), 9 10 (17.2%), 12Headache 3 (15.8%), 4 7 (17.9%), 9 10 (17.2%), 13

Skin and subcutaneous tissue disordersPruritus 4 (21.1%), 5 5 (12.8%), 5 9 (15.5%), 10Dry skin 2 (10.5%), 2 5 (12.8%), 6 7 (12.1%), 8

Rash 3 (15.8%), 4 3 (7.7%), 6 6 (10.3%), 10

Respiratory, thoracic and mediastinal disordersTachycardia 5 (26.3%), 6 3 (7.7%), 3 8 (13.8%), 9

Dyspnea 5 (26.3%), 5 2 (5.1%), 2 7 (12.1%), 7Cough 6 (31.6%), 7 7 (17.9%), 9 13 (22.4%), 16

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Table 2. Cont.

System Organ Class (SOC) and Preferred term (PT)Dose Escalation Dose Expansion Total

(N = 19) (N = 39) (N = 58)n (%), E n (%), E n (%), E

Musculoskeletal and connective tissue disordersMuscle spasms 5 (26.3%), 6 4 (10.3%), 4 9 (15.5%), 10

Blood and lymphatic system disordersAnemia 3 (15.8%), 6 6 (15.4%), 10 9 (15.5%), 16

Psychiatric disorders 4 (21.1%), 6 7 (17.9%), 12 11 (19.0%), 18Insomnia 3 (15.8%), 3 3 (7.7%), 4 6 (10.3%), 7

n = Number of patients with at least one event; E = Count of events.

Table 3. Summary of Grade 3/4 AE (AE ≥ 5%) reported in the study (Relationship-all).

Significant TEAEsDose Expansion Dose Escalation Total

(N = 19) (N = 39) (N = 58)n (%), E n (%), E n (%), E

Alanine aminotransferase increased 5 (26.3%), 5 6 (15.4%), 7 11 (19.0%), 12Aspartate aminotransferase increased 4 (21.1%), 4 7 (17.9%), 8 11 (19.0%), 12

Anemia 2 (10.5%), 2 3 (7.7%), 6 5 (8.6%), 8Neutropenia 2 (10.5%), 2 2 (5.1%), 2 4 (6.9%), 4

Hyponatremia 2 (10.5%), 2 2 (5.1%), 2 4 (6.9%), 4Thrombocytopenia 1 (5.3%), 1 2 (5.1%), 2 3 (5.2%), 3

Fatigue 1 (5.3%), 1 2 (5.1%), 3 3 (5.2%), 4

n = Number of patients with at least one event; E = Count of events. TEAEs = Treatment emergent adverse events.

Thirty-seven SAEs were reported in 22 (38%) patients in the study. Of these, six SAEs (pyrexia,International Normalization Ratio increase, sepsis syndrome, diplopia secondary to neuropathy,hypersensitivity, and skin infection) in dose expansion phase was assessed to be related to the Tenalisib.The most frequently reported SAEs were related to infections in nine (16%) patients followed bygastrointestinal disorders in five (9%) patients.

A total of seven (12%) deaths were reported in the study; however, none of them were relatedto Tenalisib. The various causes of death included hyponatremia, lung infection and sepsis inpatients who had disease progression. One death was attributed to auto-immune hemolytic anemia.The remaining three patients expired in hospice/home after being discontinued from the study due todisease progression. Two patients who experienced DLTs; were continued in the study at reduced dose(400 mg BID).

Eight TEAEs led to discontinuation of eight (14%) patients. Five TEAEs (two events of ALTincreased, rash, diplopia secondary to neuropathy, and sepsis) were related to Tenalisib and threeTEAEs (event of myelodysplastic syndrome, autoimmune hemolytic anemia, and increased AST) werenot related to Tenalisib.

3.3. Pharmacokinetics

Tenalisib was rapidly absorbed within 2 h. Cmax and AUC(0-τ) increased proportionally withdose on Cycle 1 Day 1. In the fasting cohorts, a 1.7-fold and 1.8-fold increase were observed in Cmax

between 200 mg and 400 mg BID and between 400 mg and 800 mg BID treatment cohorts on Cycle 1Day 1 respectively. Corresponding increases on Cycle 2 Day 1 were 1.8-fold and 1.1-fold. A 1.8-foldand 2.6-fold increase was observed in AUC(0-τ) between 200mg and 400 mg BID treatment cohorts,and 400 mg and 800 mg BID treatment cohorts on Cycle 1 Day 1 respectively. Exposures generallytrended higher in 800 mg BID fasting cohort compared to 800 mg BID fed cohort, this difference washowever not significant (i.e., >20%) to show a food effect.

There was no significant accumulation between Cycle 1 Day 1 and Cycle 2 Day 1. ApparentCLss/F were similar for all cohorts and ranged from 0.05–0.07 L/h with a short median t1/2 of 2.28 h

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(range 1.6 to 2.8 h). Tenalisib was not highly distributed in tissues with Vz/F similar for all cohortseven though the fed state trended a bit higher on distribution (Table 4).

Table 4. Pharmacokinetics of Tenalisib.

Parameter200 mg BID 400 mg BID 800 mg BID 800 mg BID (fed)

C1D1 C2D1 C1D1 C2D1 C1D1 C2D1 C1D1 C2D1

Cmax * (ng/mL) 1297.3 1651.4 2196.7 2897.7 3995.7 3231.5 2668.0 4165.6AUC0–∞ * (h * ng/mL) 3538.3 4018.0 6530.9 5603.9 17,363.7 17,159.4 14,538.5 14,233.8AUC(0-τ) * (h * ng/mL) 3503.0 3970.8 6415.5 5526.8 16,424.2 16,200.3 13,591.2 13,555.3

Tmax # (h) 1.0 0.5 0.8 0.5 1.1 2.1 2.1 1.1t1/2 * (h) 1.6 1.8 1.9 2.0 2.6 2.6 2.6 2.8λz (h−1) 0.4 0.4 0.4 0.4 0.3 0.3 0.3 0.3

Cmax = Maximum plasma concentration; AUC0-∞ = Area under the curve to infinity; AUC(0-τ) = Area under theplasma concentration-time curve from time of administration to the end of the dosing interval; Tmax = Time takento reach maximum concentration; t1/2 = Elimination half-life. λz = Apparent terminal elimination rate constant;BID = Twice a day; C = Cycle; D = Day. * Geometric mean; # Median.

3.4. Pharmacodynamic Assessment

As there was no Sezary syndrome patient in the dose escalation cohort at MD Anderson CancerCenter, pAKT analysis was not done.

3.5. Efficacy

Total 16 patients (7 in dose escalation and 9 in dose expansion) out of 35 evaluable patients inthe study responded to Tenalisib. ORR was 45.7% (95% CI: 28.8–63.4) among responders. CR wasreported in three (9%) patients while PR was noted in 13 (37%) patients. A total of 11 (31%) patientsexperienced SD while 8 (22.9%) experienced PD. Most of the patients responded at Cycle 3 Day 1.

The response among PTCL and CTCL patients were similar [PTCL 46.7% (95% CI: 21.3, 73.4),CTCL 45% (95% CI: 23.1, 68.5)]. Three (20%) PTCL patients achieved CR and 4 (26.7%) achieved PRwhile 9 CTCL patients achieved PR. The overall median DoR was 4.9 months (95% CI: 4.3, 12.0) with6.5 months (95% CI: 2.9, 14.9) in PTCL and 3.8 months (95% CI: 2.3, 12.8) in CTCL patients (Table 5 andFigure 2). In three PTCL patients who achieved CR, the median DoR was 13.3 months (range 7.5–18.6).

Table 5. Summary of overall response rate and duration of response.

Population Statistic

Dose Escalation DoseExpansion Cumulative

200 mg 400 mg 800 mgFasting

800 mgFed Total 800 mg

Fasting Total

All

N N = 3 N = 2 N = 3 N = 5 N = 13 N = 22 N = 35

ORR (95% CI) (%) 33.3(0.8, 90.6)

100.0(15.8, 100.0)

66.7(9.4, 99.2)

40.0(5.3, 85.3)

53.8(25.1, 80.8)

40.9(20.7, 63.6)

45.7(28.8, 63.4)

Median DoR(95% CI) (months) 4.9 (-,-) 2.4

(0.97, 3.8)10.9

(2.3, 19.5)3.3

(1.7, 4.9)3.8

(0.7, 10.2)7.5

(4.7, 15.9) 4.9 (4.3, 12.0)

CTCL

N N = 1 N = 1 N = 2 N = 4 N = 8 N = 12 N = 20

ORR (95% CI) (%) 0.0(0.0, 97.5)

100.0(2.5, 100.0)

50.0(1.3, 98.7)

50.0(6.8, 93.2)

50.0(15.7, 84.3)

41.7(15.2, 72.3)

45.0(23.1, 68.5)

Median DoR(95% CI) (months) – 3.8 (-,-) 2.3 (-,-) 3.3

(1.7, 4.9)3.05

(1.7, 4.6)10.3

(2.6, 19.6) 3.8 (2.3, 12.8)

PTCL

N N = 2 N = 1 N = 1 N = 1 N = 5 N = 10 N = 15

ORR (95% CI) (%) 50.0(1.3, 98.7)

100.0(2.5, 100.0)

100.0(2.5, 100.0)

0.0(0.0, 97.5)

60.0(14.7, 94.7)

40.0(12.2, 73.8)

46.7(21.3, 73.4)

Median DoR(95% CI) (months) 4.9 (-,-) 0.97 (-,-) 19.5 (-,-) – 4.9

(0.0, 19.5)7.0

(1.2, 17.3) 6.5 (2.9, 14.9)

N = Number of Evaluable patients; ORR = Overall Response Rate; CI = Confidence Interval, DoR = Durationof Response.

Cancers 2020, 12, 2293 10 of 14Cancers 2020, 12, x 11 of 15

Figure 2. Best response(s) to Tenalisib in PTCL and CTCL evaluable patients.

3.6. Biomarker Analysis

Analysis of plasma biomarkers from PTCL patients showed a decrease in CD30 levels from

baseline to Cycle 3 Day 1 and this correlated with response seen in these patients. For the CTCL

group, reductions were seen in plasma IL-31 and IL-32α levels at Cycle 3 Day 1 compared to baseline

and this reduction correlated with the responses seen (Figure 3).

Figure 3. Correlative biomarkers of patients treated with Tenalisib. The data presented as mean

(denoted by X) and Standard Error of Mean.

4. Discussion

In relapsed/refractory T-cell lymphomas, blockade of PI3K δ/γ isoforms at clinically achievable

concentrations could potentially inhibit T-cell activation/proliferation via inhibiting the δ isoform and

alteration of tumor microenvironment by inhibiting the γ isoform. Therefore, dual targeting of PI3K

δ/γ is a promising strategy in lymphomas. Tenalisib is a highly specific and orally available dual PI3K

δ/γ inhibitor with nanomolar inhibitory potency and several fold selectivity over α and β isoforms.

Tenalisib has been previously evaluated in a European study in relapsed/refractory patients with

hematological malignancies and showed a favorable safety profile with low incidence of adverse

events and minimal discontinuation due to TEAEs [18]. The safety profile of Tenalisib in the current

study was different from that in the European study, which did not show adverse events, such as

transaminitis and skin rash. This could be attributed to the different patient populations enrolled in

these two studies. In addition, the European study largely enrolled patients with B-cell malignancies

that could potentially account for the differences. An integrated safety analysis performed across the

two studies [22] showed that the overall incidence of the TEAEs were lower than those reported with

other PI3K inhibitors that are in development or have been FDA approved [15,23,24]. Cumulative

safety data revealed that overall incidence of immune mediated toxicities appears lower with

Tenalisib (transaminitis 10%; no events of colitis and pneumonitis) as compared to other PI3K

inhibitors (duvelisib–transaminitis 10–40%, colitis 11–18%, pneumonitis 5–20%, idelalisib-

transaminitis 16–18%, colitis 14–20%, pneumonitis 4%) [15,23,24].

Figure 2. Best response(s) to Tenalisib in PTCL and CTCL evaluable patients.

3.6. Biomarker Analysis

Analysis of plasma biomarkers from PTCL patients showed a decrease in CD30 levels frombaseline to Cycle 3 Day 1 and this correlated with response seen in these patients. For the CTCL group,reductions were seen in plasma IL-31 and IL-32α levels at Cycle 3 Day 1 compared to baseline and thisreduction correlated with the responses seen (Figure 3).

Cancers 2020, 12, x 11 of 15

Figure 2. Best response(s) to Tenalisib in PTCL and CTCL evaluable patients.

3.6. Biomarker Analysis

Analysis of plasma biomarkers from PTCL patients showed a decrease in CD30 levels from

baseline to Cycle 3 Day 1 and this correlated with response seen in these patients. For the CTCL

group, reductions were seen in plasma IL-31 and IL-32α levels at Cycle 3 Day 1 compared to baseline

and this reduction correlated with the responses seen (Figure 3).

Figure 3. Correlative biomarkers of patients treated with Tenalisib. The data presented as mean

(denoted by X) and Standard Error of Mean.

4. Discussion

In relapsed/refractory T-cell lymphomas, blockade of PI3K δ/γ isoforms at clinically achievable

concentrations could potentially inhibit T-cell activation/proliferation via inhibiting the δ isoform and

alteration of tumor microenvironment by inhibiting the γ isoform. Therefore, dual targeting of PI3K

δ/γ is a promising strategy in lymphomas. Tenalisib is a highly specific and orally available dual PI3K

δ/γ inhibitor with nanomolar inhibitory potency and several fold selectivity over α and β isoforms.

Tenalisib has been previously evaluated in a European study in relapsed/refractory patients with

hematological malignancies and showed a favorable safety profile with low incidence of adverse

events and minimal discontinuation due to TEAEs [18]. The safety profile of Tenalisib in the current

study was different from that in the European study, which did not show adverse events, such as

transaminitis and skin rash. This could be attributed to the different patient populations enrolled in

these two studies. In addition, the European study largely enrolled patients with B-cell malignancies

that could potentially account for the differences. An integrated safety analysis performed across the

two studies [22] showed that the overall incidence of the TEAEs were lower than those reported with

other PI3K inhibitors that are in development or have been FDA approved [15,23,24]. Cumulative

safety data revealed that overall incidence of immune mediated toxicities appears lower with

Tenalisib (transaminitis 10%; no events of colitis and pneumonitis) as compared to other PI3K

inhibitors (duvelisib–transaminitis 10–40%, colitis 11–18%, pneumonitis 5–20%, idelalisib-

transaminitis 16–18%, colitis 14–20%, pneumonitis 4%) [15,23,24].

Figure 3. Correlative biomarkers of patients treated with Tenalisib. The data is presented as mean(denoted by X) and Standard Error of Mean.

4. Discussion

In relapsed/refractory T-cell lymphomas, blockade of PI3K δ/γ isoforms at clinically achievableconcentrations could potentially inhibit T-cell activation/proliferation via inhibiting the δ isoform andalteration of tumor microenvironment by inhibiting the γ isoform. Therefore, dual targeting of PI3Kδ/γ is a promising strategy in lymphomas. Tenalisib is a highly specific and orally available dual PI3Kδ/γ inhibitor with nanomolar inhibitory potency and several fold selectivity over α and β isoforms.

Tenalisib has been previously evaluated in a European study in relapsed/refractory patients withhematological malignancies and showed a favorable safety profile with low incidence of adverseevents and minimal discontinuation due to TEAEs [19]. The safety profile of Tenalisib in the currentstudy was different from that in the European study, which did not show adverse events, such astransaminitis and skin rash. This could be attributed to the different patient populations enrolled inthese two studies. In addition, the European study largely enrolled patients with B-cell malignanciesthat could potentially account for the differences. An integrated safety analysis performed across thetwo studies [23] showed that the overall incidence of the TEAEs were lower than those reported withother PI3K inhibitors that are in development or have been FDA approved [15,24,25]. Cumulativesafety data revealed that overall incidence of immune mediated toxicities appears lower with Tenalisib(transaminitis 10%; no events of colitis and pneumonitis) as compared to other PI3K inhibitors

Cancers 2020, 12, 2293 11 of 14

(duvelisib–transaminitis 10–40%, colitis 11–18%, pneumonitis 5–20%, idelalisib-transaminitis 16–18%,colitis 14–20%, pneumonitis 4%) [15,24,25].

In the current study, transaminase (ALT/AST) elevations usually occurred in the first eightweeks of therapy. Most of these events were reversed by dose interruptions/dose reductions andsupportive therapy (e.g., steroid treatment). Unlike other PI3K inhibitors, late onset toxicities likecolitis, pneumonitis, and opportunistic infections were not seen with Tenalisib even in those patientstreated for more than six months, although numbers were small (29%) [23]. Five patients were ontherapy for more than 18 months and did not report any late onset immune toxicities. Though the datais limited at this juncture, there may be a different late onset safety profile emerging for Tenalisib.

In this study, the overall incidence of AEs was similar in PTCL and CTCL patient groups. However,the frequency and intensity of related AEs were higher in CTCL than in PTCL patients. A total of 27(90%) CTCL patients experienced 208 related AEs whereas 18 (64%) PTCL patients experienced 51related AE. Similarly, 12 (40%) CTCL patients experienced 25 related ≥Grade 3 AEs and 9 (32%) PTCLpatients experienced 12 related ≥Grade 3 AEs. The reason for this numerically higher incidence ofrelated AEs in CTCL patient is not clear. Further studies may be needed to understand the differencein these 2 subtypes of T-cell lymphomas.

Tenalisib was absorbed rapidly attaining peak concentrations within two hours of administration.Steady-state pharmacokinetics revealed no accumulation. A food effect study was conducted inhealthy volunteers during the course of dose escalation [26]. Data in healthy volunteers indicatedthat the presence of food (high fat meal) increased the overall exposure to Tenalisib though therewas no significant effect on Cmax [27]. Based on this data, an additional fed cohort at 800 mg BIDdose was added to determine food effect. Contrary to the healthy volunteer study, there was nomeaningful change (<20%) in the Cmax and AUC’s in the 800 mg fed and fasting cohorts, ruling outany food effect on Tenalisib in patients. In addition, the DLTs seen in the 800 mg BID fed cohortdid not correlate with pharmacokinetics as it was similar in the fasting and the fed state in patients.Given the lack of pharmacokinetic benefit as well as the presence of two DLTs in 800 mg BID fed cohort,we concluded that 800 mg BID fasting should be pursued further for expansion cohort and for allsubsequent development programs of Tenalisib.

Tenalisib showed promising anti-tumor activity in relapsed/refractory T cell lymphoma patients.The response rates were similar in CTCL and PTCL patients. Although this is the first study ofTenalisib in a T-cell population, the efficacy data seems to be similar to that of other targeted andnon-targeted agents like, romidepsin, pralatrexate and belinostat in patients with relapsed/refractoryPTCL/CTCL [10,12,28,29]. When compared to Duvelisib, the only PI3Kδ/γ inhibitor which has beenevaluated in T cell lymphoma, Tenalisib showed comparable response rates and duration of response.Although the incidence of AEs like neutropenia and transaminitis were lower with Tenalisib, only ahead to head study will enable comparisons [15,16].

Multiple studies have shown that relative decrease of sIL-2R levels correlates with time tocomplete response and is useful for early predictor of response in PTCL. High sIL-2R level predicts apoor prognosis in PTCL [30,31]. High expression of CD30 correlates with poor survival in patientswith PTCL [32]. Similarly, CTACK level in skin and sera after therapy correlates with the risk ofrecurrence [33,34]. Studies have shown that IL-31 is produced by the malignant T-cells in CTCL patientsand serum levels directly correlate with the degree of pruritus in leukemic CTCL patients. IL-32 levelspositively correlate with disease activity in CTCL patients [35,36].

We evaluated the effect of Tenalisib on the above biomarkers which correlate with diseasepathology and symptoms. There were correlative trends of reduction in CD30, IL-31, and IL-32α levelswith responses. However, there were limitations in the analysis of the data since we could not correlatedisease progression to these markers. This was due to unavailability of paired blood samples forpatients whose disease progressed before they reached Cycle 3 Day1.

Cancers 2020, 12, 2293 12 of 14

5. Conclusions

The safety and efficacy data support the development of Tenalisib as monotherapy or incombination with existing or novel targeted therapies in patients with hematological malignancies.On-going data from studies of Tenalisib as monotherapy in indolent NHL (NCT03711578) [37] and incombination with romidepsin in T-cell lymphomas (NCT03770000) [38] indicate that Tenalisib is welltolerated. With a favorable safety profile and promising clinical activity, Tenalisib holds promise as anemerging potential therapeutic option for patients with relapsed/refractory TCL.

Supplementary Materials: The following are available online at http://www.mdpi.com/2072-6694/12/8/2293/s1,Table S1: Incidence of AE (AE ≥ 5%) reported in the study (Relationship-Related).

Author Contributions: Conceptualization, P.J.B., S.V. (Srikant Viswanadha), and S.V. (Swaroop Vakkalanka), Y.O.,A.H.; Methodology, P.J.B., S.V. (Srikant Viswanadha), and S.V. (Swaroop Vakkalanka), Y.O., A.H.; Investigation, A.H.,Y.O., B.M.H., S.P.I., J.Z., R.R., M.J.L., S.D., L.P.-B., and N.J.K.; Data Curation, P.J.B., A.N., K.V.R.; Writing—OriginalDraft Preparation, P.J.B., A.N., K.V.R.; Writing—Review & Editing, A.H., Y.O., B.M.H. and S.P.I.; Supervision,S.V. (Swaroop Vakkalanka); S.P.I. All authors have read and agreed to the published version of the manuscript.

Funding: This work was supported by Rhizen Pharmaceuticals SA, La Chaux-de-Fonds, Switzerland.

Acknowledgments: The authors thank all patients and their relatives as well as investigators, research nurses,and coordinators for their contribution to this study. Med Indite Communications Pvt Ltd., Pune, India isacknowledged for their assistance in writing and technical editing of the manuscript.

Conflicts of Interest: S.P.I. has research support from Rhizen, Seattle Genetics, Spectrum (Acrotech), Affimed,Trillium, CRISPR Therapeutics, Legend Biotech, Daiichi Sankyo, Amgen and is Consultant for Daiichi Sankyo,Sanofi, Seattle Genetics and Legend Biotech. Y.O. is employed at Genentech Inc. L.P.B. have consultationwith Spectrum, Seattle Genetics, Helsin. A.N., P.J.B., K.V.R., Srikant Viswanadha are employed at RhizenPharmaceuticals. Swaroop Vakkalanka has equity, ownership and employment at Rhizen Pharmaceuticals. A.H.,has research support from Rhizen, Kyowa Kirin, Seattle Genetics, Medivir, Glaxo Smith Kline, Galderma, Miragen,and is consultant for Helsinn, Kyowa Kirin, and Seattle Genetics. S.D., B.M.H., R.R., N.J.K., J.Z., and M.J.L. havedeclared no conflicts of interest.

References

1. Swerdlow, S.H.; Campo, E.; Pileri, S.A.; Harris, N.L.; Stein, H.; Siebert, R.; Advani, R.; Ghielmini, M.;Salles, G.A.; Zelenetz, A.D.; et al. The 2016 revision of the World Health Organization classification oflymphoid neoplasms. Blood 2016, 127, 2375–2390. [CrossRef] [PubMed]

2. Vose, J.; Armitage, J.; Weisenburger, D. International T-Cell Lymphoma Project. International peripheralT-cell and natural killer/T-cell lymphoma study: Pathology findings and clinical outcome. J. Clin. Oncol.2008, 26, 4124–4130. [PubMed]

3. Abouyabis, A.N.; Shenoy, P.J.; Lechowicz, M.J.; Flowers, C.R. Incidence and outcomes of the peripheral T-celllymphoma subtypes in the United States. Leuk. Lymphoma 2008, 49, 2099–2107. [CrossRef] [PubMed]

4. Morton, L.M.; Wang, S.S.; Devesa, S.S.; Hartge, P.; Weisenburger, D.D.; Linet, M.S. Lymphoma incidencepatterns by WHO subtype in the United States, 1992-2001. Blood 2006, 107, 265–276. [CrossRef] [PubMed]

5. Park, H.S.; McIntosh, L.; Braschi-Amirfarzan, M.; Shinagare, A.B.; Krajewski, K.M. T-Cell Non-HodgkinLymphomas: Spectrum of Disease and the Role of Imaging in the Management of Common Subtypes. KoreanJ. Radiol. 2017, 18, 71–83. [CrossRef] [PubMed]

6. Poggio, T.; Duyster, J.; Illert, A.L. Current Immunotherapeutic Approaches in T Cell Non-HodgkinLymphomas. Cancers 2018, 10, 339. [CrossRef] [PubMed]

7. Mak, V.; Hamm, J.; Chhanabhai, M.; Shenkier, T.; Klasa, R.; Sehn, L.H.; Villa, D.; Gascoyne, R.D.; Connors, J.M.;Savage, K.J. Survival of patients with peripheral T-cell lymphoma after first relapse or progression: Spectrumof disease and rare long-term survivors. J. Clin. Oncol. 2013, 31, 1970–1976. [CrossRef]

8. Alpdogan, O.; Kartan, S.; Johnson, W.; Sokol, K.; Porcu, P. Systemic therapy of cutaneous T-cell lymphoma(CTCL). Chin. Clin. Oncol. 2019, 8, 10. [CrossRef]

9. Oka, T.; Miyagaki, T. Novel and Future Therapeutic Drugs for Advanced Mycosis Fungoides and SézarySyndrome. Front Med (Lausanne) 2019, 6, 116. [CrossRef]

10. O’Connor, O.A.; Pro, B.; Pinter-Brown, L.; Bartlett, N.; Popplewell, L.; Coiffier, B.; Lechowicz, M.J.; Savage, K.J.;Shustov, A.R.; Gisselbrecht, C.; et al. Horwitz Pralatrexate in patients with relapsed or refractory peripheralT-cell lymphoma: Results from the pivotal PROPEL study. J. Clin. Oncol. 2011, 29, 1182–1189. [CrossRef]

Cancers 2020, 12, 2293 13 of 14

11. Smolewski, P.; Robak, T. The discovery and development of romidepsin for the treatment of T-cell lymphoma.Expert Opin. Drug Discov. 2017, 12, 859–873. [CrossRef] [PubMed]

12. O’Connor, O.A.; Horwitz, S.; Masszi, T.; Van, H.A.; Brown, P.; Doorduijn, J.; Hess, G.; Jurczak, W.;Knoblauch, P.; Chawla, S.; et al. Belinostat in Patients With Relapsed or Refractory Peripheral T-CellLymphoma: Results of the Pivotal Phase II BELIEF (CLN-19) Study. J. Clin. Oncol. 2015, 33, 2492–2499.[CrossRef] [PubMed]

13. Prince, H.M.; Kim, Y.H.; Horwitz, S.M.; Dummer, R.; Scarisbrick, J.; Quaglino, P.; Zinzani, P.L.; Wolter, P.;Sanches, J.A.; Ortiz-Romero, P.L.; et al. ALCANZA study group. Brentuximab vedotin or physician’schoice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): An international, openlabel, randomised,phase 3, multicentre trial. Lancet 2017, 390, 555–566. [CrossRef]

14. Katsuya, H.; Cook, B.M.L.; Rowan, A.G.; Satou, Y.; Taylor, G.P.; Bangham, C.R. Phosphatidylinositol3-kinase-δ (PI3K-δ) is a potential therapeutic target in adult T-cell leukemia-lymphoma. Biomark. Res. 2018,6, 24. [CrossRef] [PubMed]

15. Horwitz, S.M.; Koch, R.; Porcu, P.; Oki, Y.; Moskowitz, A.; Perez, M.; Myskowski, P.; Officer, A.; Jaffe, J.D.;Morrow, S.N.; et al. Activity of the PI3K-delta, gamma inhibitor duvelisib in a phase 1 trial and preclinicalmodels of T-cell lymphoma. Blood 2018, 131, 888–898. [CrossRef]

16. Flinn, I.W.; O’Brien, S.; Kahl, B.; Patel, M.; Oki, Y.; Foss, F.F.; Porcu, P.; Jones, J.; Burger, J.A.; Jain, N.; et al.A novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies. Blood2018, 131, 877–887. [CrossRef]

17. Lewis, J.; Girardi, M.; Vakkalanka, S.; Viswanadha, S.; Bertoni, F. RP6530, a dual PI3Kδ/γ inhibitor, attenutatesAKT phosphorylation and induces apoptosis in primary cutaneous T cell lymphoma (CTCL) cells. Blood2013, 22, 4418. [CrossRef]

18. Mao, G.; Viswanadha, S. Rhizen, Switzerland. Unpublished work, 2013.19. Carlo-Stella, C.; Delarue, R.; Scarfo, L.; Barde, P.J.; Nair, A.; Locatelli, S.L.; Morello, L.; Magagnoli, M.;

Vakkalanka, S.; Viswanadha, S.; et al. A first-in-human study of Tenalisib (RP6530), a dual PI3K δ/γ inhibitor,in patients with relapsed/refractory hematologic malignancies: Results from the European study. Clin.Lymphoma Myeloma Leuk. 2020, 20, 78–86. [CrossRef]

20. Compassionate Use Study of Tenalisib (RP6530). Available online: https://clinicaltrials.gov/ct2/show/

NCT03711604. (accessed on 15 July 2020).21. Cheson, B.D.; Pfistner, B.; Juweid, M.E.; Gascoyne, R.D.; Specht, L.; Horning, S.J.; Coiffier, B.; Fisher, R.I.;

Hagenbeek, A.; Zucca, E.; et al. International Harmonization Project on Lymphoma. Revised responsecriteria for malignant lymphoma. J. Clin. Oncol. 2007, 25, 579–586. [CrossRef]

22. Olsen, E.A.; Whittaker, S.; Kim, Y.H.; Duvic, M.; Prince, H.M.; Lessin, S.R.; Wood, G.S.; Willemze, R.;Demierre, M.F.; Pimpinelli, N.; et al. Clinical end points and response criteria in mycosis fungoides andSézary syndrome: A consensus statement of the International Society for Cutaneous Lymphomas, the UnitedStates Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the EuropeanOrganisation for Research and Treatment of Cancer. J. Clin. Oncol. 2011, 29, 2598–2607.

23. Iyer, S.P.; Huen, A.; Ferreri, A.J.M.; Haverkos, B.M.; Zain, J.M.; Ramchandren, R.; Lechowicz, M.J.; Devata, S.;Korman, N.; Pinter-Brown, L.C.; et al. Pooled safety analysis and efficacy of Tenalisib (RP6530), a PI3K δ/γ

inhibitor in patients with relapsed/refractory lymphoid malignancies. Blood 2018, 132, 2925. [CrossRef]24. Duvelisib: Prescribing information. 2018. Available online: https://www.accessdata.fda.gov/drugsatfda_

docs/label/2018/211155s000lbl.pdf (accessed on 14 July 2020).25. Idelalisib: Prescribing information. 2014. Available online: https://www.accessdata.fda.gov/drugsatfda_

docs/label/2014/206545lbl.pdf (accessed on 14 July 2020).26. To Evaluate the Food Effect on Relative Bioavailability of RP6530 in Healthy Volunteers. Available online:

https://clinicaltrials.gov/ct2/show/NCT02690727 (accessed on 15 July 2020).27. Barde, P. Rhizen, Switzerland. Unpublished work, 2016.28. Coiffier, B.; Pro, B.; Prince, H.M.; Foss, F.; Sokol, L.; Greenwood, M.; Caballero, D.; Morschhauser, F.;

Wilhelm, M.; Pinter-Brown, L.; et al. Romidepsin for the treatment of relapsed/refractory peripheral T-celllymphoma: Pivotal study update demonstrates durable responses. J. Hematol. Oncol. 2014, 7, 1–9. [CrossRef][PubMed]

Cancers 2020, 12, 2293 14 of 14

29. Foss, F.; Pro, B.; Prince, H.M.; Sokol, L.; Caballero, D.; Horwitz, S.; Coiffier, B. Responses to romidepsin byline of therapy in patients with relapsed or refractory peripheral T-cell lymphoma. Cancer Med. 2017, 6,36–44. [CrossRef] [PubMed]

30. Kitagawa, J.; Hara, T.; Tsurumi, H.; Goto, N.; Kanemura, N.; Yoshikawa, T.; Kasahara, S.; Yamada, T.;Sawada, M.; Takahashi, T.; et al. Serum-soluble IL-2 receptor (sIL-2R) is an extremely strong prognosticfactor for patients with peripheral T-cell lymphoma, unspecified (PTCL-U). J. Cancer Res. Clin. Oncol. 2009,135, 53–59. [CrossRef] [PubMed]

31. Morita-Fujita, M.; Katoh, D.; Shimomura, Y.; Ishikawa, T. High Level of Serum Soluble Interleukin-2 ReceptorIs Associated With Poor Survival in Patients With First Relapsed or Refractory Peripheral T-Cell Lymphoma,Not Otherwise Specified: A Retrospective Study. Clin. Lymphoma Myeloma Leuk. 2019, 19, e337–e342.[CrossRef]

32. Maura, F.A.; Dodero, A.; Carniti, C.; Bolli, N. Biology of peripheral T cell lymphomas—Not otherwisespecified: Is something finally happening? Pathogenesis 2016, 3, 9–18. [CrossRef]

33. Fujita, Y.; Abe, R.; Sasaki, M.; Honda, A.; Furuichi, M.; Asano, Y.; Norisugi, O.; Shimizu, T.; Shimizu, H.Presence of Circulating CCR10+ T cells and Elevated Serum CTACK/CCL27 in the Early Stage of MycosisFungoides. Clin. Cancer Res. 2006, 12, 2670–2675. [CrossRef]

34. Hu, S.C.S. Mycosis fungoides and sezary syndrome: Role of chemokines and chemokine receptors. World. J.Dermatol. 2015, 4, 69–79. [CrossRef]

35. Cedeno-Laurent, F.; Singer, E.M.; Wysocka, M.; Benoit, B.M.; Vittorio, C.C.; Kim, E.J.; Yosipovitch, G.;Rook, A.H. Improved pruritus correlates with lower levels of IL-31 in CTCL patients under differenttherapeutic modalities. Clin. Immunol. 2015, 158, 1–7. [CrossRef]

36. Suga, H.; Sugaya, M.; Miyagaki, T.; Kawaguchi, M.; Fujita, H.; Asano, Y.; Tada, Y.; Kadono, T.; Sato, S. The roleof IL-32 in cutaneous T-cell lymphoma. J. Investig. Dermatol. 2014, 134, 1428–1435. [CrossRef]

37. Efficacy and Safety Study of Tenalisib (RP6530), a Novel PI3K δ/γ Dual Inhibitor in Patients WithRelapsed/Refractory Indolent Non-Hodgkin’s Lymphoma (iNHL). Available online: https://clinicaltrials.gov/

ct2/show/NCT03711578 (accessed on 15 July 2020).38. Safety and Efficacy of Tenalisib (RP6530) in Combination with Romidepsin in Patients with

Relapsed/Refractory T-cell Lymphoma. Available online: https://clinicaltrials.gov/ct2/show/NCT03770000(accessed on 15 July 2020).

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